DESCRIPTION: This proposal centers on the synthesis of novel cross-bridged tetraamine ligands that are designed to bind small cations strongly and selectively. Target health-related applications include clinical sensors, nuclear medicine, and bioinorganic chemistry. The specific aims are: I. To design and synthesize cross-bridged tetraamines with one or two pendant arms for enhanced cation binding. Ligands having additional enveloping binding groups will allow fine-tuning of steric and electronic properties, metal coordination geometry, and covalent bonding of conjugates for biolocalization. II. To make structural modifications of the parent structures for increased Li+/Na+ and Mg2+/Ca2+ selectivity. Modifications predicted to increase selectivity include backbone benzo annulation and introduction of certain N-substituents. III. To investigate the metal binding of these new ligands, the reactivity of resulting complexes, and potential applications. The stability and selectivity of main group (Li+, Mg2+, Zn2+, In3+) and transition metal (Cu2+, Ni2+, Co2+,3+) binding will be studied for each family of ligands. Use of the ligands for ion-selective sensing of both Li+ and Mg2+ will be explored. Radioisotopes of two of these metals (In and Cu) are potential radiopharmaceuticals. Possible reactions of biological relevance at the metal centers will be examined. IV. To synthesize linked binucleating or "earmuff" tetraamine ligands based upon the bicyclic tetraamine structural motifs. The ligands themselves and their immediate synthetic precursors are of potential application as anti-HIV agents. Their bimetallic complexes can model active sites in several metalloenzymes.